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Spinel-orthopyroxene symplectites are common throughout a >1,200-m-thick sequence of the Rustenburg Layered Suite in the Waterberg project area in the far north of the northern limb of the Bushveld Complex. The symplectites occur between primocrysts of olivine and spinel in the presence of plagioclase in the assemblage. The composition of spinel in the symplectites varies with host rock and increasing stratigraphic height: in the lower parts of the stratigraphy spinel is represented by Cr-poor chromite, the spinel is Cr magnetite in more evolved rocks, and in the most evolved rocks the spinel is magnetite. Olivine and clinopyroxene in the assemblage with the symplectites are partially resorbed and surrounded by an orthopyroxene rim in the lower part of the sequence, whereas a complex mantle of clinopyroxene-hornblende-phlogopite has developed around the orthopyroxene rims in evolved rocks. Preferential extension of orthopyroxene lamellae over host clinopyroxene results in common stepped boundaries toward either olivine or plagioclase. The symplectites and other disequilibrium microtextures are interpreted to be the result of the infiltration of a reactive melt, which destabilized the ferromagnesium minerals and spinel. The aureoles with symplectites are associated and spatially coincident with two zones of high-grade platinum group element (PGE) sulfide mineralization of the Waterberg project. Both mineralized intervals occur in lithologies and at stratigraphic intervals that are unique within the Bushveld Complex. Stratiform magmatic mineralization of the lower F zone was partly remobilized upward from ultramafic rocks by migrating melts, whereas PGE-rich sulfides of the upper T zone were likely derived during the reactive melt flow into the resident crystal mush.

The precipitation of phosphoric acid from nitric acid solutions in the presence of iron(3+) oxides and hydroxyoxides under hydrothermal conditions was studied. It was shown that the dephosphorization process proceeds with the formation of iron(3+) hydroxyphosphate (giniite) Fe5(PO4)4(OH)3∙2H2O. The most efficient and fast process is implemented at temperatures of 180-200 °C and above. It was found that the content of phosphoric acid in the solution as a result can be reduced to 10-3 mol/l and below. Lanthanide, uranium, and thorium nitrates are stable under conditions of hydrothermal dephosphorization of solutions, in contrast to iron(3+) nitrates decomposing to hematite and nitric acid. The features of the studied hydrothermal process were used to increase the efficiency of direct nitric acid leaching of monazite iron-bearing ores of the Chuktukon rare metal deposit.

The problem of maximum stresses estimation in the weld metal, where the direct measurements are not possible due to the influence of the metal structure on the measurement error, was solved. The influence of features of welding joints manufacturing technology on the structure of the weld metal was also determined. We use several reference welded joints of pipelines at nuclear power plants in our studies. Instrumental estimation of acoustoelasticity parameters in the weld metal in welded joints and in adjacent areas of the base metal was used together with computational modeling of the residual welding stresses distributions. Results obtained demonstrate that the error of stress measurement in the metal in the joint, which is related to the structure of the weld metal, is comparable to the material yield strength. Due to that a direct measurement of the maximum values of welding stresses is not possible. Comparison of results of acoustoelasticity parameters measurements with results of the metal macrostructure studies and mechanical tests allowed us to determine the relationship between peculiarities of structure of the weld metal sections at vertical joints with their tendency to brittle destruction. We propose and justify the NDT method of residual welding stresses in the weld metal. It is based on the principle of residual stresses balancing and employs the results of stress measurements in the base metal by acoustoelasticity. Applicability of non-destructive testing of acoustoelasticity parameters to identify the areas of welded joints with a higher tendency to brittle fracture is also justified.

Controlling the ratio of capacitance and power of supercapacitors by changing the composition of the electrodes will allow to create optimal power systems for specific applications. For the formation of such electrodes, a method is required that combines the possibilities of creating a multicomponent composite with a high degree of uniformity of composition and morphology over the layer thickness. An example of such a method can be the eco-friendly method of electrophoretic deposition used in this work, which makes it possible to locally deposit a composite material from multicomponent suspensions at room temperature. We present an approach related to electrophoretic deposition from a suspension of composite material SuperC-RuO 2 , in which the ratio of the components can be changed to vary the proportion of electrochemical and electrical double layer storage. Nanocarbon, which has a large surface area, and ruthenium oxide with a significant electrochemical capacity, in combination, will allow combining high power and capacity in one device, and their ratio will determine the proportion of electrochemical and electrical double layer storage. In this work, approaches are investigated and recommendations are given for increasing the stability of suspensions, the effect of the composition of the suspension on the composition of composite electrodes and their capacitive and power characteristics is determined.

The paper discusses the issue of optimizing the work of a traffic light that regulates the movement of vehicles at an intersection. For this, a discrete-event model of vehicle traffic has been developed. The architecture and content of the model, its interface and graphical parts are described. To test the work of the model, a real intersection of Yasnyy proezd—Dezhneva street in Moscow is used. In order to improve the operation of the intersection, an optimization experiment was carried out using the model. As an objective function during optimization, we used the minimum average time for cars to pass through the intersection. The obtained results of the conducted research allow drawing the following conclusions: a direct increase in traffic intensity several times (+200%) does not have a significant effect on the efficiency of the intersection operation (average time for cars to pass through the intersection, average number of cars at the intersection); the minimum average time for cars to pass through the intersection is 54.66 s. It is achieved with the following parameter values (traffic light phase operating times): TL1 = 50 s and TL2 = 20 s; at the moment, the work of the traffic light provides a high efficiency of vehicle passage. However, a slight adjustment of the phase operation time will slightly reduce (~2 s) the time for cars to pass through the intersection. The following tools were used: AnyLogic software simulation environment, Java object-oriented programming language, OptQuest optimizer, Google Maps mapping service.

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8+ T��cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T��cells, enhanced effectiveness of bi-specific T��cell engaging antibodies, and improved CAR T��cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T��cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.

The article analyzes the experience of organizing high-speed rail services in China, the current state and development prospects. An analysis of open sources and publications on this topic is carried out. The characteristics of the infrastructural support of the most significant transport facilities of high-speed rail transportation are given and the question of further development of high-speed rail service in People’s Republic of China is considered. An assessment is made of the economic and social significance of China’s high-speed railway lines.

Significance Voltage-gated ion channels contain domains that have discrete functionalities. The central pore domain allows current flow and provides ion selectivity, whereas peripherally located voltage-sensing domains (VSDs) are needed for voltage-dependent gating. Certain mutations trigger a leak current through VSDs, known as gating pore current. Hypokalemic periodic paralysis (HypoPP) type 2 is caused by mutations in the skeletal muscle voltage-gated sodium channel NaV1.4 that neutralize positive charges in S4 voltage-sensing segments of VSDs. We show that Hm-3 toxin from the crab spider Heriaeus melloteei inhibits gating pore currents through such mutant channels. We propose that Hm-3 and similar toxins may constitute useful hits in developing gating pore current inhibitors and HypoPP therapy., Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3–S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.

The paper discusses the prospects for the use of the Northern Sea Route as an option of the transit cargo transportation in international traffic in the conditions of the development of alternative means of communication and the global economic environment of the transport market. The reasons for the low demand for the Northern Sea Route are analyzed. The demand for transportation is predicted.

A new suite of 173 clinopyroxene grains from heavy-mineral concentrates of the diamondiferous Novinka kimberlite (Upper Muna field, Yakutia) has been analyzed for major and minor elements with an electron microprobe to perform a thermobarometric study and model the thermal structure of the Archean Upper Muna lithospheric mantle. Scrupulous evaluation of propagation of analytical uncertainties on pressure estimates revealed that (1) the single-clinopyroxene geobarometer can be very sensitive to analytical uncertainties for particular clinopyroxene compositions, and that (2) most clinopyroxenes from Novinka have compositions that are sensitive to analytical uncertainties, notwithstanding their apparent compositional suitability for single-clinopyroxene thermobarometry based on previously proposed application limits. A test on various mantle clinopyroxenes containing different proportions of the sensitive elements Cr, Na, and Al allowed us to identify clinopyroxene compositions that produce unacceptably high propagated errors and to define appropriate analytical conditions (i.e., higher beam currents and longer counting times for specific elements) that allow precise P-T estimates to be obtained for sensitive compositions. Based on the results of our analytical test, and taking into account the intrinsic limitations of the single-clinopyroxene thermobarometer, we have designed a new protocol for optimum thermobarometry, which uses partly revised compositional filters. The new protocol permits precise computation of the conductive paleogeotherm at Novinka with the single-clinopyroxene thermobarometer of Nimis and Taylor (2000). Thermal modeling of the resulting P-T estimates indicates a similar to 34 mW/m(2) surface heat flow, a thermal lithosphere thickness of similar to 225 km, and an over 100 km thick "diamond window" beneath Novinka in the middle Paleozoic (344-361 Ma). We estimate that appropriate analytical conditions may extend the applicability of single-clinopyroxene thermobarometry to over 90% of clinopyroxene-bearing garnet peridotites and pyroxenites and to similar to 70% of chromian-diopside inclusions in diamonds. In all cases, application to clinopyroxenes with Cr/(Cr+Al)(mol) < 0.1 is not recommended. We confirm the tendency of the single-clinopyroxene barometer to progressively underestimate pressure at P > 4.5 GPa.

Gamma-band oscillations are implicated in modulation of attention and integration of sensory information. The finding that cross-regional coherence varies with task and performance suggests a role for gamma oscillations in flexible communication among anatomically connected brain areas. How networks become entrained is incompletely understood. Specifically, it is unclear how the spectral and temporal characteristics of network oscillations can be altered on rapid timescales needed for efficient communication. We use closed-loop optogenetic modulation of principal cell excitability to interrogate the dynamical properties of hippocampal oscillations. Gamma frequency and amplitude can be modulated bi-directionally, and dissociated, by phase-advancing or delaying optogenetic feedback to pyramidal cells. Closed-loop modulation alters the synchrony rather than average frequency of action potentials, in principle avoiding disruption of population rate-coding of information. Modulation of phasic excitatory currents in principal neurons is sufficient to manipulate oscillations, suggesting that feed-forward excitation of pyramidal cells has an important role in determining oscillatory dynamics and the ability of networks to couple with one another.

Аннотация На современном этапе большое внимание уделяется изучению психологического благополучия в различных группах населения, однако работы, посвященные оценке пси-хологического благополучия и психологического здоровья у спортсменов малочисленны. В медицинском смысле понимание качества жизни всегда связано со здоровьем, так как здоровье служит его основным показателем. Соответственно для самооценки здоровья можно пользоваться опросником качества жизни, связанного со здоровьем SF-36. В руководстве по исследованию качества жизни связанного со здоровьем рекоменду-ется использование методики SF-36 не только в медицинских исследованиях, но и для «оценки состояния здоровья как населения в целом, так и отдельных социальных групп». Методика «позволяет дать количественную оценку многокомпонентных характеристик жизнедеятельности человека – его физического, психологического и социального функ-ционирования» Ключевые слова

107 отношений на формирование физических и нравственно-этических качеств, и закрепле-ние опыта нравственного поведения и привычек, нормы морали. ЛИТЕРАТУРА 1. Ахияров, К.Ш. Народная педагогика и современная школа / К.Ш. Ахияров ; Башкирский гос. пед. ун-т. – Уфа : [б.и.], 2000. – 328 с. 2. Змановская, Е.В. Девиантология / Е.В. Змановская. – М. : Академия, 2008. – 287 с. 3. Миннегалиев, М.М. Физкультурно-оздоровительная деятельность в школе как средство профилактики девиантного поведения несовершеннолетних : автореф. дис. … канд. пед. наук / Миннегалиев М.М. – Уфа, 2004. – 20 с. 4. Соломченко, М.А. Основы управления физической культурой и спортом в со-временных социально-экономических условиях : учеб. пособие / М.А. Соломченко, Р.А. Прохоров. – Орел : Изд-во Орловского гос. ун-та, 2009. – 148 c. 5. Юричка, Ю.И. Девиантология: конфликты, агрессия, наркомания, правонару-шения : монография / Ю.И. Юричка, А.Ю. Юричка ; Мос. гос. открытый пед. ун-т. – М. : Изд-во МГОПУ, 2001. – 164 с. REFERENCES 1. Ahijarov, K.S. (2000)

The nonapeptide-receptor interaction energy calculated from docking algorithms was compared with the effect of the same peptides upon solute-free water reabsorption in rat kidney in vivo. Vasotocin and some of its analogs were injected intramuscularly into conscious female Wistar rats in doses from 0.1 pmol to 0.5 nmol/kg of body weight after oral water load (50 ml/kg of body weight). A significant correlation was found between the calculated energy of peptide interaction with V2 receptors and an increase in the renal solute-free water reabsorption stimulated by injection of nonapeptides. The results evidence that physiological changes in rat kidney in vivo induced by vasotocin analogs can be accurately simulated by virtual modeling of their interactions with V2 receptors.

The Cys-loop receptor family consists of nicotinic acetylcholine receptors (nAChR), glycine receptor, GABA-A and some other receptors. They fulfill a plethora of functions, whereas their malfunctioning is associated with many diseases. All three domains - extracellular ligand-binding, membrane and cytoplasmic - of these ligand-gated ion channels play important roles in the receptor assembly, delivery to the membrane surface and functional activity. In this study, we discuss the role of these domains in the assembly of the Cys-loop receptors, most comprehensively for the nAChRs. Heterologous expression and mutations of large N-terminal fragments of various subunits demonstrated their leading role in the assembly, although getting an isolated well-structured pentameric ligand-binding domain is still a problem. The long intracellular loop between transmembrane fragments M3 and M4 participates in modulating the receptor function and in clusterization of the receptor complexes because of interactions with the intracellular proteins. The transmembrane fragments play different functional roles: M2 fragments outline the channel, M4 fragments, the most remote from the channel, modulate the channel function and contact the lipid environment. The interactions of aromatic residues in the M1 and M3 fragments with those of M4 are important for the correct assembly of glycine receptor α1 subunit and for the formation of functional pentaoligomer. The role of the three receptor domains is discussed in the light of electron microscopy structure of the Torpedo nAChR, X-ray structures of agonist and antagonist complexes with the acetylcholine-binding proteins and the X-ray structures of the prokaryotic Cys-loop receptors.

Weak toxins are the "three-fingered" snake venoms toxins grouped together by having an additional disulfide in the N-terminal loop I. In general, weak toxins have low toxicity, and biological targets have been identified for some of them only, recently by detecting the effects on the nicotinic acetylcholine receptors (nAChR). Here the methods of docking and molecular dynamics simulations are used for comparative modeling of the complexes between four weak toxins of known spatial structure (WTX, candoxin, bucandin, gamma-bungarotoxin) and nAChRs. WTX and candoxin are those toxins whose blocking of the neuronal alpha7- and muscle-type nAChR has been earlier shown in binding assays and electrophysiological experiments, while for the other two toxins no such activity has been reported. Only candoxin and WTX are found here to give stable solutions for the toxin-nAChR complexes. These toxins appear to approach the binding site similarly to short alpha-neurotoxins, but their final position resembles that of alpha-cobratoxin, a long alpha-neurotoxin, in the complex with the acetylcholine-binding protein. The final spatial structures of candoxin and WTX complexes with the alpha7 neuronal or muscle-type nAChR are very similar and do not provide immediate answer why candoxin has a much higher affinity than WTX, but both of them share a virtually irreversible mode of binding to one or both these nAChR subtypes. Possible explanation comes from docking and MD simulations which predict fast kinetics of candoxin association with nAChR, no gross changes in the toxin conformation (with smaller toxin flexibility on alpha7 nAChR), while slow WTX binding to nAChR is associated with slow irreversible rearrangement both of the tip of the toxin loop II and of the binding pocket residues locking finally the toxin molecule. Computer modeling showed that the additional disulfide in the loop I is not directly involved in receptor binding of WTX and candoxin, but it stabilizes the structure of loop I which plays an important role in toxin delivery to the binding site. In summary, computer modeling visualized possible modes of binding for those weak toxins which interact with the nAChR, provided no solutions for those weak toxins whose targets are not the nAChRs, and demonstrated that the additional disulfide in loop I cannot be a sound criteria for joining all weak toxins into one group; the conclusion about the diversity of weak toxins made from computer modeling is in accord with the earlier phylogenetic analysis.

This paper analyzes the approaches taken by the Russian government to promote innovation in the biotechnology sector within the country. Russia is economically strong, currently with a trade surplus, and the country is investing broadly in initiatives that have resulted in in-bound technology transfer, as well as an expansion of the private sector. These initiatives include government venture capital and investment funds, as well as physical technology “incubator” centers. The result has been an increase in the number of clinical-stage biotechnology companies operating in Russia, as well as an increase in the number of pharmaceutical candidates undergoing trials in the country. The biotechnology “boom” has also resulted in an increase in the number of early-stage companies. This paper investigates current deal and investment trends from the funds that are the principal supporters of biotechnology companies in Russia.

Cys-loop receptors (CLR) are pentameric ligand-gated ion channels that mediate fast excitatory or inhibitory transmission in the nervous system. Strychnine and d-tubocurarine (d-TC) are neurotoxins that have been highly instrumental in decades of research on glycine receptors (GlyR) and nicotinic acetylcholine receptors (nAChR), respectively. In this study we addressed the question how the molecular recognition of strychnine and d-TC occurs with high affinity and yet low specificity towards diverse CLR family members. X-ray crystal structures of the complexes with AChBP, a well-described structural homolog of the extracellular domain of the nAChRs, revealed that strychnine and d-TC adopt multiple occupancies and different ligand orientations, stabilizing the homopentameric protein in an asymmetric state. This introduces a new level of structural diversity in CLRs. Unlike protein and peptide neurotoxins, strychnine and d-TC form a limited number of contacts in the binding pocket of AChBP, offering an explanation for their low selectivity. Based on the ligand interactions observed in strychnine- and d-TC-AChBP complexes we performed alanine-scanning mutagenesis in the binding pocket of the human α1 GlyR and α7 nAChR and showed the functional relevance of these residues in conferring high potency of strychnine and d-TC, respectively. Our results demonstrate that a limited number of ligand interactions in the binding pocket together with an energetic stabilization of the extracellular domain are key to the poor selective recognition of strychnine and d-TC by CLRs as diverse as the GlyR, nAChR, and 5-HT3R., Author Summary Ligand-gated ion channels play an important role in fast electrochemical signaling in the brain. Cys-loop receptors are a class of pentameric ligand-gated ion channels that are activated by specific neurotransmitters, including acetylcholine (ACh), serotonin (5-HT), glycine (Gly), and γ-aminobutyric acid (GABA). Each type of cys-loop receptor contains an extracellular domain that specifically recognizes only one of these four neurotransmitters and opens an ion-conducting channel pore upon ligand binding. In this study, we investigated the poor specificity with which two potent neurotoxic inhibitors, namely strychnine and d-tubocurarine, are recognized by different cys-loop receptors. Using X-ray crystallography we solved 3-dimensional structures of strychnine or d-tubocurarine in complex with ACh binding protein (AChBP), a well-recognized structural homolog of the nicotinic ACh receptor. Based on ligand-receptor interactions observed in AChBP structures we designed mutant GlyR and α7 nAChR to identify hot spots in the binding pocket of these receptors that define potent inhibition by strychnine and d-tubocurarine, respectively. Combined, our results offer detailed understanding of the molecular recognition of antagonists that have high affinity but poor specificity for different cys-loop receptors.

Cys-loop receptors are pentameric ligand-gated ion channels (pLGICs) that mediate fast synaptic transmission. Here functional pentameric assembly of truncated fragments comprising the ligand-binding N-terminal ectodomains and the first three transmembrane helices, M1-M3, of both the inhibitory glycine receptor (GlyR) alpha1 and the 5HT(3)A receptor subunits was found to be rescued by coexpressing the complementary fourth transmembrane helix, M4. Alanine scanning identified multiple aromatic residues in M1, M3 and M4 as key determinants of GlyR assembly. Homology modeling and molecular dynamics simulations revealed that these residues define an interhelical aromatic network, which we propose determines the geometry of M1-M4 tetrahelical packing such that nascent pLGIC subunits must adopt a closed fivefold symmetry. Because pLGIC ectodomains form random nonstoichiometric oligomers, proper pentameric assembly apparently depends on intersubunit interactions between extracellular domains and intrasubunit interactions between transmembrane segments.

The divalent cation copper (Cu2+) has been shown to inhibit chloride currents mediated by the inhibitory glycine receptor (GlyR). Here, we analyzed Cu2+ inhibition of homo- and hetero-oligomeric GlyRs expressed in Xenopus oocytes. No significant differences in Cu2+ inhibitory potency were found between alpha1, alpha2 and alpha3 GlyRs as well as heteromeric alpha1beta receptors. Furthermore, GlyR alpha1 mutations known to reduce inhibition or potentiation of GlyR currents by Zn2+ had no effect on Cu2+ inhibition. However, Cu2+ was found to competitively antagonize glycine binding, suggesting that Cu2+ binds at the agonist-binding site. Mutations within the glycine-binding site of the GlyR alpha1 subunit reduced the inhibitory potency of Cu2+ and led to an up to 4-fold potentiation of glycine-elicited currents by Cu2+. Molecular dynamics simulation suggests this to be due to increased Cu2+ binding energies. Our data show that GlyR binding-site mutations can convert inhibitors of agonist binding into highly effective positive modulators.

Cys-loop receptors, also designated pentameric ligand-gated ion channels (pLGICs) include nicotinic acetylcholine receptors (nAChRs), serotonin type 3 receptors (5HT3Rs), γ-amino butyric acid type-A receptors (GABAARs) and glycine receptors (GlyRs). pLGICs function as obligate pentamers linked by non-covalent interactions between the N-terminal extracellular domains of identical or homologous subunits. Here we show that expression of GlyR α1 or 5HT3A subunits in two separate fragments (one containing the ectodomain and transmembrane domains M1-M3, and the other the fourth transmembrane domain M4) results in the assembly of functional pLGICs indistinguishable in their electrophysiological properties from wt pLGICs assembled from contiguous subunits. Alanine scanning of M1, M3 and M4 of the GlyR α1 subunit identified a total of 12 aromatic residues as important or crucial for pentameric assembly. The assembly-relevant aromatic residues cluster in one face of each helix. Homology modelling based on crystal structures (Hilf & Dutzler 2008; Bocquet et al 2008) predicted π- π interactions between the aromatic face of the M4 helix and three or two aromatic residues located in the M1 helix (Tyr228, Trp239, and Phe242) and the M3 helix (Trp286, Phe293), respectively. The loss of homopentamer formation and function seen upon alanine replacement of any of these contact residues strongly supports the existence of a membrane-embedded network of pairwisely interacting aromatic side chains that compacts and stabilizes the membrane core region of the GlyR. We infer from these results that a precise geometric arrangement of transmembrane helices defined by the tri-helical aromatic network is a prerequisite to allow the circular arrangement of the subunits stabilized essentially by earlier occurring random subunit interactions between the ectodomains.